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Antibiotic resistance among major pathogens
compared to hospital treatment guidelines and
antibiotic use in Nordic hospitals 2010–2018
Vidar Möller, Åse Östholm-Balkhed, Dag Berild, Mats Fredriksson, Magnus
Gottfredsson, Martin Holmbom, Asko Järvinen, Mar Kristjansson, Ulf Rydell,
Ute Wolff Sönksen, Hans Joern Kolmos & Håkan Hanberger
To cite this article: Vidar Möller, Åse Östholm-Balkhed, Dag Berild, Mats Fredriksson, Magnus Gottfredsson, Martin Holmbom, Asko Järvinen, Mar Kristjansson, Ulf Rydell, Ute Wolff Sönksen, Hans Joern Kolmos & Håkan Hanberger (2021) Antibiotic resistance among major pathogens compared to hospital treatment guidelines and antibiotic use in Nordic hospitals 2010–2018, Infectious Diseases, 53:8, 607-618, DOI: 10.1080/23744235.2021.1910338
To link to this article: https://doi.org/10.1080/23744235.2021.1910338
© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
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NO. 8, 607–618
ORIGINAL ARTICLE
Antibiotic resistance among major pathogens compared to hospital treatment
guidelines and antibiotic use in Nordic hospitals 2010
–2018
Vidar M€oller
a, Åse €
Ostholm-Balkhed
a, Dag Berild
b,c, Mats Fredriksson
a, Magnus Gottfredsson
d,e,
Martin Holmbom
a, Asko J€arvinen
f, Mar Kristjansson
d,e, Ulf Rydell
a, Ute Wolff S€onksen
g,
Hans Joern Kolmos
hand Håkan Hanberger
aa
Department of Biomedical and Clinical Sciences, Faculty of Medicine, Link€oping University, Link€oping, Sweden;bDepartment of Infectious Diseases, Oslo University Hospital, Oslo, Norway;cInstitute of Clinical Medicine, University of Oslo, Oslo, Norway;
d
Landspitali University Hospital, Reykjavik, Iceland;eUniversity of Iceland, Reykjavik, Iceland;fDivision of Infectious Diseases, Helsinki University Hospital and Helsinki University, Helsinki, Finland;gStatens Serum Institut, Copenhagen, Denmark;hOdense University Hospital, Odense, Denmark
ABSTRACT
Background: The Nordic countries have comparable nationwide antibiotic resistance surveillance systems and individual antibiotic stewardship programmes. The aim of this study was to assess antibiotic resistance among major pathogens in relation to practice guidelines for hospital antibiotic treatment and antibiotic use in Nordic countries 2010–2018.
Methods: Antibiotic resistance among invasive isolates from 2010–2018 and aggregated antibiotic use were obtained from the European Centre for Disease Prevention and Control. Hospital practice guidelines were obtained from national or regional guidelines.
Results: Antibiotic resistance levels among Escherichia coli and Klebsiella pneumoniae were similar in all Nordic countries in 2018 and low compared to the European mean. Guidelines for acute pyelonephritis varied; 2nd generation cephalosporin (Finland), 3rd generation cephalosporins (Sweden, Norway), ampicillin with an aminoglycoside or aminoglycoside mono-therapy (Denmark, Iceland and Norway). Corresponding guidelines for sepsis of unknown origin were 2nd (Finland) or 3rd (Sweden, Norway, Iceland) generation cephalosporins, carbapenems, (Sweden) combinations of penicillin with an aminogly-coside (Norway, Denmark), or piperacillin-tazobactam (all Nordic countries). Methicillin-resistant Staphylococcus aureus rates
were 0–2% and empirical treatment with anti-MRSA antibiotics was not recommended in any country. Rates of penicillin
non-susceptibility among Streptococcus pneumoniae were low (<10%) except in Finland and Iceland (<15%), but benzylpe-nicillin was recommended for community-acquired pneumonia in all countries.
Conclusion: Despite similar resistance rates among Enterobacteriaceae there were differences in practice guidelines for pyelonephritis and sepsis. National surveillance of antibiotic resistance can be used for comparison and optimization of guidelines and stewardship interventions to preserve the low levels of antibiotic resistance in Nordic countries.
KEYWORDS Antibiotic resistance practice guidelines as topic antibiotic stewardship Nordic countries ARTICLE HISTORY Received 14 November 2020 Revised 9 March 2021 Accepted 11 March 2021 CONTACT Håkan Hanberger hakan.hanberger@liu.se
This Original Article accompanies the Editorial Commentary– Surveillance: a prerequisite for effective antimicrobial stewardship, also in this issue. Supplemental data for this article can be accessedhere.
ß 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
Introduction
Antibiotic resistance (ABR) is a global health problem, and the World Health Organisation (WHO) has devel-oped a global action plan to tackle ABR. The action plan aims to improve awareness and understanding of anti-biotic resistance, to strengthen knowledge through sur-veillance and research, to reduce the incidence of infection, to optimize the use of antibiotic agents, and to support sustainable investment in new medicines, diagnostic tools, vaccines and other interventions [1].
The Nordic countries have a long history of nation-wide antibiotic resistance surveillance programmes, and collaboration with the European Centre for Disease
Prevention and Control (ECDC) [2–5]. ECDC compiles
data on ABR and antibiotic consumption submitted by the European countries. Thus data from the Nordic countries can be compared with other European coun-tries except Switzerland, on the ECDC website [6].
Antibiotic stewardship first started in Iceland in the field of veterinary medicine, leading to a ban on the use of antibiotics as livestock growth promoters in 1978. This was followed by Sweden in the 80s and Norway in the 90s [7], while the Danish and Finnish livestock indus-try voluntarily stopped the use of growth promoters
during the 90s [8]. Antibiotic stewardship in human
medicine was introduced in 1995 in Sweden in the form of STRAMA (Strategy Group for the Rational Use of Antibiotics and Reduction of Antibiotic Resistance). This was a reaction to clonal outbreaks of antibiotic resist-ance among Streptococcus pneumoniae and the
increas-ing use of antibiotics in community care [9]. At the
same time, an outbreak of macrolide resistance among Streptococcus pyogenes led to a nationwide campaign to reduce macrolide use in Finland [10].
It is well established that antibiotic use is an import-ant driver of import-antibiotic resistance [11]. To optimise the use of antibiotics, treatment guidelines must be adapted
to resistance levels [12]. However, comparison of ABR
with practice guidelines (PG) for antibiotic treatment in
Nordic hospitals has, to our knowledge, never
been evaluated.
The aim of this study was to assess ABR among major pathogens in relation to hospital PGs and antibiotic use in Nordic hospitals 2010–2018.
Material and methods
This study covered all Nordic countries, that is, Denmark, Finland, Iceland, Norway and Sweden.
Antibiotic susceptibility
Susceptibility patterns for Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), Staphylococcus aureus (S. aureus) and Streptococcus pneumoniae (S. pneumoniae) in blood and spinal fluid were acquired from the ECDC Surveillance Atlas of Infectious Diseases,
as well as national reports for the years
2010–2018 [2–6].
For E. coli and K. pneumoniae, data were obtained for resistance to 3rd generation cephalosporins, fluoroqui-nolones, aminoglycosides and carbapenems. For S. aur-eus, data were obtained for methicillin-resistant S. aureus (MRSA), and for S. pneumoniae, resistance to macrolides and penicillin non-susceptibility (PNSP).
Additionally, resistance rates among E. coli and K. pneumoniae to piperacillin-tazobactam and 2nd
gener-ation cephalosporins were obtained from national
reports when available. This information provided per-centages not actual numbers of resistant isolates, and statistical analyses could not be performed.
Definitions of susceptibility and resistance were
according to EUCAST [13], and only data on resistance
are shown, apart from PNSP which includes both resist-ant isolates and isolates with decreased susceptibility.
Due to the lack of a universal standard for antibiotic susceptibility testing on any specific bacterial species, sample sizes may differ between antibiotic classes from year to year as local microbiology labs in collaboration with clinicians decide which antibiotics to test.
Antibiotic consumption
Data on antibiotic consumption based on sales statistics were obtained from the European Surveillance System
(TESSy) [14]. Antibiotic consumption was divided into
community care and hospital care. Community con-sumption refers to all antibiotics prescribed in general practice. Icelandic data were provided as total
consump-tion 2010–2013 and community consumption for
2014–2018. Hospital consumption constituted 10–11%
of the total consumption according to the Icelandic Medicines Agency [15].
Antibiotic consumption was measured as a defined daily dose (DDD) per 1000 inhabitants per day (DID) as described by WHO [16].
The broad-spectrum antibiotic was defined as a ceph-alosporin, carbapenem, combinations of penicillin and beta-lactamase inhibitor, and fluoroquinolone.
Practice guidelines (PG) for antibiotic treatment in hospitals
Hospital care in Denmark is organized into five regions, each having guidelines for the empirical use of antibiotics. In this survey, national sepsis guidelines from 2017 were accessed from the Danish Society of Infectious Diseases
[17] while regional (Hovedstaden, Midtjylland, Nord,
Sjaelland, and Syddanmark) PGs in hospitals were accessed from the Danish Society of Clinical Microbiology [18] and merged: treatment recommendations occurring in at least two regional guidelines were included. For individual
Danish regional guidelines, see Supplement 1. Regional
Danish PGs were updated as follows: Hovedstaden 2018,
Midtjylland 2019, Nord 2019, Sjaelland 2018 and
Syddanmark 2019. Finland has regional PGs, but only those from the Hospital District of Helsinki and Uusimaa (HUS)
[19], updated 2017, were used. The Norwegian government
agency’s (Helsedirektoratet) national hospital guidelines
from 2018 were used [20]. Sweden has a national PG
issued by the Swedish Society of Medicine, Section for
Infectious Diseases [21] and STRAMA [22] and these,
updated as of 2019, were included. PGs for hospital use of antibiotics in Iceland were provided and updated in 2019 by the Director of Infectious Diseases at Landspitali University Hospital, Reykjavik (Personal communication from Kristjansson M).
The most recently available PGs were grouped according to indications.
Pneumonia was divided into two subcategories: com-munity-acquired pneumonia with high and low mortality risk using the scoring system CRB-65 (or CURB 65 in
Denmark and Iceland) where 0–2 (0–2) points is defined
as low mortality risk and 3–4 (3–5) defined as high risk
for mortality requiring intensive care.
Guidelines for sepsis of unknown origin have been issued by all countries. Norway and Finland use systemic
inflammatory response syndrome (SIRS) criteria [23] or
modified SIRS criteria to define sepsis and septic shock. Denmark, Sweden, and Iceland use Sepsis 3 criteria on the sequential organ failure assessment score (SOFA) [24].
Pyelonephritis was divided into two subcategories: pyelonephritis without complications or with complica-tions/urosepsis.
Statistical analysis
Antibiotic resistance over time and DID over time were analyzed using linear regression. Analyses were carried out with Stata/MP 14.1, StataCorp LLC, College Station,
TX, USA. A p-value <.05 was considered statistically sig-nificant. All significant changes described in the results relate to significant trends over the study period.
Results
Antibotic resistance: trends and levels in 2018
Resistance rates for each pathogen and the respective antibiotics are presented country-wise inTables 1–4.
In 2010, Denmark had the highest 3rd generation
cephalosporin, fluoroquinolone and aminoglycoside
resistance among E. coli, but these levels did not change significantly during the study period. In contrast, 3rd generation cephalosporin, fluoroquinolone and amino-glycoside resistance among E. coli increased significantly in Sweden, Norway, and Finland. Sample sizes in Iceland were small and no changes in resistance rates among the species examined reached statistical significance.
In 2018, resistance to 3rd generation cephalosporin in invasive isolates of E. coli was highest in Sweden (8.3%) and lowest in Norway (6.8%).
Denmark likewise had the highest 3rd generation
cephalosporin, fluoroquinolone, and aminoglycoside
resistance levels among K. pneumoniae, but over the study period aminoglycoside and 3rd generation ceph-alosporin resistance decreased significantly. Apart from Denmark, no decrease in antibiotic resistance among K. pneumoniae was seen, whereas resistance to fluoro-quinolones increased in Finland, resistance to 3rd gener-ation cephalosporins and aminoglycosides increased in Norway, and resistance to 3rd generation cephalospor-ins, fluoroquinolones and aminoglycosides increased in Sweden.
In 2018, resistance to 3rd generation cephalosporins among K. pneumoniae was highest in Norway (7.5%) and lowest in Finland (4.5%) There were too few isolates in Iceland to be valid in any comparison.
MRSA rates were 0–2.0%, the highest (2.0%) being in
Finland and lowest (0.9%) in Norway. The rates of PNSP were highest in Finland (11.5%) followed by Iceland
(9.7%), Denmark (5.5%), Sweden (5.2%), and
Norway (5.0%).
Practice guidelines for antibiotic treatment in hospitals
Practice guidelines country-wise for selected indications are shown inTable 5.
Table 1. Escherichia coli in blood and spinal fluid samples, 2010–2018.
Resistance amongE. coli in blood and spinal fluid samples (%)
2010 2011 2012 2013 2014 2015 2016 2017 2018 p-Value Sample sizes (n) Denmark
Fluoroquinolones 13.7 14.1 14.1 12.4 12.3 11.9 11.0 12.8 13.3 .245 3166–5386 3rd generation Cephalosporins 7.6 8.5 7.9 8.1 7 7.5 6.6 6.9 7.7 .294 2408–4883 Aminoglycosides 5.8 6.4 7.3 6.5 7.3 6.8 6.1 6.0 5.8 .764 3412–5393
Carbapenems 0 0 0 0 0 0 0.0 0.0 0 N/A 2011–5117
Piperacillin and inhibitor N/A N/A N/A N/A N/A N/A 4.0 4.5 3.8 N/A 4838–5113 Finland
Fluoroquinolones 9.2 11 11.7 13.2 11 11.2 11.5 12.0 11.4 .001 2550–5305 2nd generation Cephalosporins 4.6 7.2 8.6 10 8.1 8.2 9.0 9.8 10.7 N/A 3019–5286 3rd gen Cephalosporins 3.7 5 6.2 7.1 5.4 6.1 6.9 6.9 7.6 <.001 2509–5223 Aminoglycosides 3.8 5.2 6.1 6.5 4.6 5.4 4.9 5.0 4.3 .028 2356–4982
Carbapenems 0 0 0 0 0 0 0.0 0 0 N/A 2471–5315
Piperacillin and inhibitor 2.3 2.7 2.3 2.6 2.1 2.2 1.5 1.6 1.5 N/A 2332–5397 Iceland Fluoroquinolones 10.5 14 9.7 14.7 7.8 6.8 9.6 11.6 17.2 .805 95–199 3rd generation Cephalosporins 3.8 6.2 5.1 5 3.3 1.7 4.2 6.1 8.1 .419 104–213 Aminoglycosides 2.9 6.2 3.6 4.1 5.3 2.9 3.6 5.6 6.1 .3 104–213 Carbapenems 0 0 0 0 0 0 0 0 0 N/A 0–52 Norway Fluoroquinolones 8.7 9 11.3 10.9 11 10.2 10.9 13.6 12.9 <.001 2267–3877 3rd generation Cephalosporins 3.7 3.6 4.9 5.5 5.8 6 5.6 5.9 6.8 <.001 2275–3879 Aminoglycosides 4.3 4.1 5.8 6.4 5.9 6 5.5 7.2 5.8 <.001 2246–3880 Carbapenems 0 0 0 0.1 0 0 0.1 0.1 0 N/A 2089–3879
Piperacillin and inhibitor N/A N/A N/A N/A N/A N/A 1.9 1.5 2 N/A 1940–2136 Sweden
Fluoroquinolones 10.5 10.1 11.1 11.6 11.3 12.6 13.7 15.8 18.1 <.001 3998–7356 3rd generation Cephalosporins 2.9 3.6 4.5 5.2 5.6 6.2 8.3 7.4 8.3 <.001 4470–7532 Aminoglycosides 3.4 4.8 5.8 6 6.1 6.4 7.2 6.5 7.7 <.001 4239–7100
Carbapenems 0 0 0 0 0 0.1 0.1 0.0 0 N/A 3866–7347
Piperacillin and inhibitor N/A N/A N/A N/A 2.3 2.7 3.3 3.0 2.7 N/A 5149–6285 Data from the European Surveillance System– TESSy, provided by Denmark, Finland, Iceland, Norway, and Sweden, and released by ECDC. p-Value <.05 indicates significant change compared to 2010 levels.
Antibiotics not monitored by ECDC, and reported as presented by national reports. Piperacillin and inhibitor refer to a combination of piperacillin and a beta-lacta-mase inhibitor.
Table 2. Klebsiella pneumoniae in blood and spinal fluid samples, 2010–2018.
Resistance rates amongK. pneumoniae in blood and spinal fluid samples (%)
2010 2011 2012 2013 2014 2015 2016 2017 2018 p-Value Sample sizes Denmark
Fluoroquinolone 11.3 11.6 8.8 8.9 6.9 5.3 5.3 9.1 8.5 .155 673–1279 3rd generation cephalosporins 10.6 11.1 10.5 11.5 7.6 7.8 7.5 7.3 6.5 .03 529–1159 Aminoglycosides 6.1 5.8 6.0 4.4 4.9 2.6 3.2 3.2 3.3 .003 799–1278
Carbapenems 0 0 0.3 0.2 0.2 0 0.3 0.3 0.5 N/A 491–1185
Piperacillin and inhibitor N/A N/A N/A 6 8 6 6 7.4 6.1 N/A 879–1280 Finland
Fluoroquinolone 2.5 2.7 2.1 2.6 4.6 3.3 2.7 7.9 6.3 .001 401–808 3rd generation cephalosporins 4 2.5 1.7 2.2 2.4 3 4.1 4.6 4.5 .679 397–805 Aminoglycosides 3.8 1.2 0.4 1.7 2.3 1.9 2.3 2.9 2.6 .458 372–774
Carbapenems 0 0 0 0 0 0 0.3 0.3 0.6 N/A 391–810
Piperacillin and inhibitor 2.1 3.2 2.8 1.8 2.6 2 2.2 2.4 2.5 N/A 317–758 Iceland
Fluoroquinolone 0 4.2 7.1 0 3.6 2.9 0 6.3 0 N/A 14–35
3rd generation cephalosporins 3.7 7.7 21.4 0 0 0 0 5.9 0 N/A 14–36
Aminoglycosides 0 0 0 0 3.6 0 0 11.8 0 N/A 16–36 Carbapenems 0 0 0 0 0 0 0 0 0 N/A 0–13 Norway Fluoroquinolone 7.4 3.5 4 4.9 6.2 5 4.3 10.2 13.1 .102 427–808 3rd generation cephalosporins 2.1 2.9 3.2 4 5.9 5 5.8 5.8 7.5 .004 421–811 Aminoglycosides 1.7 2.8 2.4 2.3 4.8 3.6 3.3 4.2 5.3 .021 426–809 Carbapenems 0 0 0.5 0.2 0 0.1 0 0 0.1 N/A 443–810
Piperacillin and inhibitor 1.1 2.6 0.7 2.6 2.9 2.3 3.7 2.9 3.5 N/A 454–685 Sweden
Fluoroquinolone 5.8 3.8 3.7 3.9 4.1 4.5 5.4 9.8 10.1 .004 742–1533 3rd generation cephalosporins 2.4 2.3 2.9 3.6 4.5 3.3 4.9 5.6 5.5 .001 842–1537
Aminoglycosides 1.6 2.0 2.5 2.9 3.3 3.2 3.4 4.7 3 .001 795–1235
Carbapenems 0.3 0 0.1 0 0 0 0.1 0.1 0.2 N/A 708–1531
Piperacillin and inhibitor N/A N/A N/A N/A 4 3.8 4.1 4.1 6.9 N/A 958–1035 Data from the European Surveillance System– TESSy, provided by Denmark, Finland, Iceland, Norway, and Sweden, and released by ECDC. p-Value <.05 indicates significant trend during the study period.
Sepsis of unknown origin
Norway and Denmark recommended a combination of benzylpenicillin or ampicillin and an aminoglycoside, while Sweden recommended cefotaxime or piperacillin-tazobactam ± an aminoglycoside. Finnish guidelines did not include an aminoglycoside. All countries considered piperacillin-tazobactam a treatment option, and all except Denmark recommended cephalosporins, either 2nd (Finland) or 3rd generation (Iceland, Norway, and Sweden). Empirical treatment with anti-MRSA drugs was not included in any of the guidelines.
Pyelonephritis
Sweden recommended monotherapy with ceftibuten,
tri-methoprim-sulfamethoxazole or ciprofloxacin, or as
intravenous alternatives cefotaxime,
piperacillin-tazobac-tam, or an aminoglycoside. Finland recommended
monotherapy with cefuroxime, oral ciprofloxacin or piperacillin-tazobactam for complicated cases. Denmark, Norway and Iceland recommended an aminoglycoside
combined with ampicillin. Danish guidelines also
included a combination of mecillinam and an
aminoglycoside. Norwegian guidelines had trimetho-prim/sulfamethoxazole as an option.
Norwegian guidelines define pyelonephritis with com-plications as febrile infection of the upper urinary tract combined with septic symptoms, functional or anatom-ical abnormalities in the urinary tract, diabetes mellitus, immune deficiency/cytostatics, or pregnancy. Icelandic guidelines did not specify complications.
Swedish and Danish PGs did not have the concept of pyelonephritis with complications but offered recommen-dations for urosepsis, that is, comparable to ‘septic symp-toms’ in the Norwegian definition. For pyelonephritis with complications or urosepsis, recommendations were as fol-lows: Danish guidelines included piperacillin-tazobactam; Norwegian guidelines included ampicillin together with gentamicin or cefuroxime as an alternative; while Swedish and Icelandic guidelines included carbapenems.
Community-acquired pneumonia CRB-65/CURB-65 0–2 All guidelines recommended benzylpenicillin. When atypical pneumonia is suspected, a fluoroquinolone or macrolide was advised.
Table 3. Streptococcus pneumoniae in blood and spinal fluid samples, 2010–2018.
Resistance amongS. pneumoniae in blood and spinal fluid samples (%)
2010 2011 2012 2013 2014 2015 2016 2017 2018 p-Value Sample sizes Denmark PNSP 3.6 4.8 5.1 6.6 5.6 4.7 6.1 3.9 5.5 .057 707–954 Macrolides 4.1 5.0 5.8 4.8 6.6 5.2 4.8 3.6 2.5 .597 707–954 Finland PNSP 14.2 12.9 17.0 13.9 12.5 12.7 10.3 10.5 11.5 .185 553–706 Macrolides 27.0 24.5 21.8 18.3 14.2 14.0 11.4 15.0 12.1 <.001 607–808 Iceland PNSP 5.4 9.4 3.7 16.7 8.0 24.0 10.5 18.5 9.7 .523 18–37 Macrolides 10.8 21.9 7.4 16.7 12.5 12.0 0.0 18.5 12.9 .422 18–37 Norway PNSP 3.7 3.4 5.9 3.3 5.1 5.4 4.4 4.8 5.0 .289 429–619 Macrolides 3.7 4.0 5.3 3.8 4.3 4.0 5.3 5.5 7.6 .184 403–570 Sweden PNSP 3.7 3.3 5.1 6.8 7.9 9.8 7.1 6.1 5.2 .157 420–1016 Macrolides 3.9 4.5 4.7 6.2 6.2 6.6 5.3 4.7 4.5 .420 750–1030
Data from the European Surveillance System– TESSy, provided by Denmark, Finland, Iceland, Norway and Sweden, and released by ECDC. Streptococcus pneumoniae with resistance to macrolides and/or decreased susceptibility to penicillin.p-Value <.05 indicates significant trend during the study period.
Table 4. Methicillin-resistantStaphylococcus aureus (MRSA) in blood and spinal fluid samples 2010–2018. Methicillin-resistantStaphylococcus aureus (MRSA) in blood and spinal fluid samples (%)
2010 2011 2012 2013 2014 2015 2016 2017 2018 p-Value Sample sizes Denmark MRSA 1.3 1.2 1.3 1.7 2.5 1.6 2.0 2.5 1.7 .441 1362–2181 Finland MRSA 2.3 3.2 2.1 1.8 2.6 1.9 2.2 2.0 2.0 .591 1094–2439 Iceland MRSA 1.5 2.8 1.7 0.0 3.3 0.0 1.3 1.4 0 .999 58–88 Norway MRSA 0.6 0.3 1.3 0.7 1.0 1.2 1.2 1.0 0.9 .349 1047–1547 Sweden MRSA 0.5 0.8 0.7 1.0 1.0 0.8 2.3 1.2 1.9 <.001 2662–4099
Data from the European Surveillance System– TESSy, provided by Denmark, Finland, Iceland, Norway and Sweden, and released by ECDC. p-Value <.05 indicates significant trend during the study period.
Community-acquired pneumonia CRB-65/CURB-65 3–4/3–5
Norway recommended a combination of benzylpenicillin and an aminoglycoside, with the addition of a macrolide when suspecting Mycoplasma or Legionella. Iceland, Finland, and Sweden recommended a cephalosporin combined with either a fluoroquinolone or a macrolide.
Denmark recommended either benzylpenicillin or
piperacillin-tazobactam combined with a macrolide.
Recommendations on when to cover ESBL-producing bacteria were as follows
Swedish (STRAMA) PG state conditions when ESBL-produc-ing pathogens should be covered: previous infection or col-onization caused by ESBL-forming bacteria in the last 6 months; stay in countries with a high prevalence of ESBL-producing bacteria in the last 6 months; or inpatient care in hospitals outside the Nordic region in the last 6 months.
Norwegian PG recommended carbapenem treatment when there is a high prevalence of ESBL-producing Enterobacteriaceae locally.
Danish National sepsis PG: when the patient has been abroad within the last three months, contact the infec-tious disease department regarding possible resistance. No regional PGs gave advice regarding ESBL.
Icelandic PG: contact infectious disease department when suspecting resistant pathogen based on patient his-tory, such as previous colonization with ESBL-produc-ing bacteria.
Finnish PG: Prior hospitalization; broad-spectrum anti-biotic therapy in the previous 3 months; known carrier or family member of the known carrier of a multi-resistant bacteria; or previous hospitalization outside the country.
Antibiotic consumption
Overview of total and community antibiotic
consumption
Overall, 88% of all antibiotics consumed in the Nordic countries 2018 were prescribed within community care, and 12% in-hospital care.
Community- and hospital-prescribed antibiotic con-sumption figures over the study period for each country
Table 5. Empirical practice guidelines for hospital use.
Antibiotic Sweden Norway Denmark Finland Iceland
Sepsis of unknown origin
Ampicillinþ gentamicin ± metronidazole x
Penicillinþ gentamicin x Cefuroxime x Cefotaxime x x Ceftriaxone ± metronidazole x Piperacillin-tazobactam x x x x x Imipenem/meropenem x Pyelonephritis/urosepsis Aminoglycoside x Ampicillinþ gentamicin x x x Mecillinamþ gentamicin x Cefuroxime c x 3rd generation cephalosporin x c x Ceftibuten x Ciprofloxacin x x Trimethoprim-sulfamethoxazole x x Piperacillin-tazobactam x c x Carbapenem c c
Pneumonia community-acquired CRB 65 0-2, CURB 65 0-2
Benzylpenicillin x x x x x
Amoxicillin ± clavulanic acid x
Cefuroxime x
Pneumonia community-acquired CRB 65 3-4, CURB-65 3-5
Penicillinþ fluoroquinolone x
Penicillinþ aminoglycoside ± macrolide x
Penicillinþ macrolide x
3rd generation cephalosporine ± macrolide x x x
Ceftriaxoneþ fluoroquionolone x
Cefuroximeþ fluoroquinolone x
Piperacillin-tazobactamþ macrolide x
Treatment recommended by country marked by an ‘X’. Sweden/Norway/Denmark: add aminoglycoside in septic shock or when at risk for developing septic shock. In sepsis with unknown focus, four out of 5 danish regions recommended ampicillin and gentamicin and two regions additionally recommended considering combination with metronidazole, and all regions recommended piperacillin-tazobactam. For pyeloneph-ritis, one Danish region recommended monotherapy only with mecillinam, three of 5 mecillinam and gentamicin, two of 5 ampicillin and genta-micin, and one recommended monotherapy with piperacillin-tazobactam as an alternative. In addition, for urosepsis, four of 5 regions advised ampicillin and gentamicin, and four of 5 monotherapy with piperacillin-tazobactam (two regions recommended only one of these two options). c: pyelonephritis with complications/urosepsis.
are shown in Table 6. There was a significant decrease
in community consumption in Denmark, Finland,
Norway and Sweden over the study period. Iceland
sub-mitted total consumption data for 2010–2013 and
com-munity consumption from 2014 and onwards, so no trend could be calculated. In 2018, Iceland had the high-est community-prescribed antibiotic consumption (20.45 DID) and Sweden the lowest (10.78 DID). Community consumption figures in Norway, Denmark and Finland were similar (13.98, 13.61 and 13.17 DID respectively). Community consumption of fluoroquinolones was high-est in Iceland (0.82 DID) followed by Finland (0.62 DID), Sweden (0.61 DID), Denmark (0.41 DID), and lowest in
Norway (0.32 DID). Fluoroquinolone consumption
decreased in all five Nordic countries.
Hospital antibiotic consumption
The most common antibiotic classes used in the Nordic
hospitals in 2018 are shown in Figure 1. There was a
slight but significant decrease in hospital antibiotic sumption in Finland over the study period, but the con-sumption (2.28 DID) remained the highest in 2018, followed by Denmark (1.94 DID), Sweden (1.65 DID), and Norway (1.30 DID).
Beta-lactamase-sensitive penicillin (benzylpenicillin)
and beta lactamase-resistant penicillin (isoxazolylpenicil-lins) as well as penicillins with extended-spectrum (ampi-cillin and amoxi(ampi-cillin), were commonly used in all Nordic hospitals. In 2018, penicillins constituted 53% of the total hospital antibiotic consumption in Sweden, while
the corresponding figure for Norway was 44%, for Denmark 39%, and Finland 18%.
The use of first-generation cephalosporins (i.e. cefa-lexin and cefalotin) was highest in Finland (0.12 DID), followed by Norway (0.09 DID), while use in Denmark and Sweden was close to zero. Finland was the highest consumer of 2nd generation cephalosporins, mainly cefuroxime, at 0.74 DID. This was also the most com-monly used antibiotic in-hospital care in Finland. The use of 2nd generation cephalosporins in Sweden and Norway was very low (0.01 and 0.02 DID respectively),
whereas consumption in Denmark was 10–20 times
higher (0.17 DID) but still less than half of that in Finland. The use of 3rd generation cephalosporins was highest in Norway (0.13 DID) followed by Sweden (0.11 DID) and Finland (0.09 DID), while use in Denmark (0.03 DID) was less than 25% of Norwegian consumption.
Combinations of penicillin and a beta-lactamase inhibitor (amoxicillin with clavulanic acid and piperacillin with tazobactam) increased in all countries between 2010 and 2018, with the largest increase being in Denmark from 0.12 to 0.32 DID. The lowest use, and increase, was in Norway from 0.02 in 2010 to 0.06 DID in 2018.
The use of fluoroquinolones in hospitals was highest in Finland (0.20 DID), followed by Sweden (0.14 DID), Denmark (0.13 DID), and lastly Norway (0.04 DID).
Among antibiotics not shown in Figure 1, the
con-sumption of aminoglycosides was highest in Norway (0.08 DID) followed by Denmark (0.04 DID) and Sweden
(0.02 DID), and lowest in Finland (0.01 DID).
Table 6. Antibiotic consumption measured as defined daily dose per 1000 inhabitants per day, aggregated data from all anti-biotic classes. Antibiotic consumption 2010 2011 2012 2013 2014 2015 2016 2017 2018 p-Value Denmark 17.509 18.305 17.305 17.539 17.150 17.501 17.007 16.240 15.551 Community 15.876 16.692 15.705 16.660 15.176 15.310 15.166 14.334 13.611 .001 Hospital sector 1.633 1.614 1.653 1.880 1.974 2.191 1.841 1.906 1.939 .047 Finland 19.726 21.513 20.638 19.554 19.103 18.118 17.412 15.701 15.444 Community 17.014 18.555 17.983 16.927 16.594 15.763 15.034 13.592 13.166 <.001 Hospital sector 2.711 2.958 2.655 2.626 2.509 2.356 2.378 2.109 2.278 .001
Iceland 19.818 19.812 19.667 19.438 N/A N/A N/A N/A N/A
Community N/A N/A N/A N/A 17.112 17.588 18.167 18.845 20.450 N/A
Hospital sector N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A
Norway 16.803 17.531 17.928 17.184 16.906 16.790 16.232 15.742 15.279 Community 15.406 16.106 16.533 15.831 15.544 15.432 14.893 14.366 13.982 .007 Hospital sector 1.396 1.425 1.395 1.352 1.362 1.357 1.339 1.376 1.297 .010 Sweden 15.203 15.413 15.279 14.245 13.972 13.514 13.231 12.772 12.435 Community 13.756 13.886 13.709 12.650 12.481 11.924 11.673 11.258 10.783 <.001 Hospital sector 1.447 1.527 1.571 1.595 1.491 1.590 1.558 1.514 1.652 .120 Total consumption in bold. Iceland reported only total consumption 2010–2013, and thereafter only community consumption. Data from the European Surveillance System – TESSy, provided by Denmark, Finland, Iceland, Norway and Sweden, and released by ECDC. p-Value <.05 indicates significant trend during the study period.
N/A: not available.
Broad-spectrum antibiotics defined as carbapenems, cephalosporins, combinations of a penicillin and beta-lactam inhibitor, and fluoroquinolones. Significant decrease; Significant increase.
Corresponding figures for macrolides were in Denmark 0.12 DID, Finland 0.07 DID, Norway 0.03 DID, and Sweden 0.02 DID.
Broad-spectrum antibiotic consumption as a propor-tion of total hospital consumppropor-tion was 58% in Finland, followed by 36% in Denmark, 28% in Norway, and 25% in Sweden.
Discussion
Antibiotic resistance levels among major pathogens causing bacteraemia were similar in all Nordic countries in 2018, and low compared to other European countries, whereas antibiotic consumption and PGs differed widely (except community-acquired pneumonia). In 2018, the European population-weighted mean of 3rd generation resistant E. coli (ESBL phenotype) was 15%, but only
7–8% in the Nordic countries. Likewise, 31% of K.
pneu-moniae strains were ESBL phenotype in Europe, but only
5–8% in the Nordic countries. The mean European MRSA
rate was 17%, but only 0–2% in the Nordic countries
[25]. While ESBL-producing E. coli is mainly associated
with travel and migration followed by a spread in the community, K. pneumoniae is more often a nosocomial
pathogen. Thus, the link between aggregated antibiotic use in hospitals and antibiotic resistance among E. coli
and K. pneumoniae must be assessed separately.
Furthermore, antibiotic consumption in outpatient care constitutes 90% of total consumption and thus likely to have a greater impact on resistance among E. coli than hospital consumption. Even though both hospital and community fluoroquinolone consumption decreased in all countries during the study period, fluoroquinolone resistance in E. coli continued to increase and was above 10% in 2018. This makes fluoroquinolones no longer a first-line choice for empirical monotherapy in pyeloneph-ritis or urosepsis.
All Nordic countries except Denmark recommended a 2nd or 3rd generation cephalosporin for pyelonephritis or sepsis, where E. coli and K. pneumoniae are the two major pathogens. If the rates of cephalosporin-resistant (ESBL-producing) Enterobacteriaceae continue to rise, treatment strategies will have to shift. The inclusion of
piperacillin-tazobactam for pyelonephritis in PG in
Sweden, Denmark, and Finland bears witness to this. Although Nordic countries have low antibiotic resistance rates among E. coli and K. pneumoniae they are not exempted from the global ESBL pandemic and should Hospital consumpon of anbiocs 2018
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 Denmark Finland Norway Sweden
Figure 1 Defined daily dose per 1000 inhabitants per day of the 10 most commonly used antibiotic groups of the 5th ATC level in the Hospital sector 2018. Data from the European Surveillance System – TESSy, provided by Denmark, Finland, Norway and Sweden, and released by ECDC. No data available from Iceland on hospital consumption of antibiotics.
therefore comply with multitarget actions proposed by WHO in the future [1,26].
The consumption of combinations of penicillin and a beta-lactamase inhibitor (amoxicillin with clavulanic acid and piperacillin-tazobactam) increased in all countries between 2010 and 2018, the largest increase being in Denmark. This may be the result of measures taken to reduce the selective pressure of cephalosporins and qui-nolones on ESBL-producing and quinolone-resistant Enterobacteriaceae. Carbapenem consumption increased
in Denmark in 2012–2013 and has remained high ever
since. Since carbapenems are the most reliable treat-ment option for ESBL-producing E. coli and K. pneumo-niae, an increase in use will probably be seen in all Nordic countries following the global increase in ESBL-producing Enterobacteriaceae. However, it is important to consider and find carbapenem-saving alternatives such as temocillin and new beta-lactam inhibitor combi-nations [27,28].
Finland, in contrast to all other Nordic countries, did not recommend adding an aminoglycoside to beta-lac-tam antibiotics in empirical therapy for sepsis with or without septic shock. A Cochrane meta-analysis and recent mainly observational studies have shown that a combination of a beta-lactam antibiotic with an amino-glycoside does not provide any survival benefit for patients with sepsis compared to beta-lactam monother-apy, but does increase the risk for nephrotoxicity
[29–31]. A large study using propensity scoring showed
that adding an aminoglycoside to a beta-lactam
(exclud-ing broad-spectrum beta-lactams with effect on
Pseudomonas aeruginosa such as carbapenems),
increased survival in septic shock [32]. Combination ther-apy is still recommended in surviving sepsis guidelines and several national guidelines [33–35], and there is still
debate on whether to add an aminoglycoside [36]. A
recently published Swedish retrospective single-centre study showed lower mortality in sepsis with or without septic shock when using combinations of various beta-lactam antibiotics and an aminoglycoside, compared to
monotherapy [37]. Thus, there is still a knowledge gap
if, when, and for which beta-lactam antibiotics to add an aminoglycoside in sepsis, which explains the
varia-tions in PG’s. Pyelonephritis PG’s in Denmark, Norway
and Iceland recommended a combination of aminogly-coside and beta-lactam antibiotics as an alternative to broad-spectrum beta-lactam monotherapy.
Antibiotic stewardships have several goals, including optimization of clinical outcomes; lowered costs; and
minimizing unintended consequences of antibiotic
therapy such as toxicity, Clostridium difficile diarrhoea, and the emergence of antibiotic-resistant bacteria [38]. This may be implemented, for example, by promoting compliance to PG including use of narrow-spectrum antibiotics while still effective, and surveillance of anti-biotic use and resistance. Data on antianti-biotic exposure of the individual patient are needed to evaluate appropri-ate use but were not available in this study. This made it difficult to determine any causal relationship between, for example, consumption of 3rd generation cephalo-sporins and risk for emergence of ESBL-producing E. coli and K. pneumoniae. Even so, it is important to monitor antibiotic use and promote the use of narrow-spectrum antibiotics, since it is well known that broad-spectrum antibiotics have a negative effect on the microbiome and are a risk factor for the emergence of antibiotic resistance [39]. National antibiotic resistance data are also crucial when revising national antibiotic treatment guidelines. Furthermore, aggregated antibiotic consump-tion may also be used as one parameter when evaluat-ing stewardship interventions, or to identify the need for such interventions.
The rates of PNSP in Finland were more than three times higher than in Sweden, Norway and Denmark in 2010 and twice as high at the end of the study. The Icelandic PNSP rates varied greatly over the study period but were similar to Finnish levels in 2018. Increases in PNSP and macrolide-resistant S. pneumoniae in Finland are considered to be mainly due to the expansion of
several clones [40–42]. However, studies have also
shown a correlation between antibiotic use and PNSP [43,44]. Finland had a significant reduction in commu-nity consumption of antibiotics and slightly decreased PNSP rates during the study period. That may have been caused by several factors beyond the reduced con-sumption such as the Finnish pneumococcal vaccination program [45]. A similar decrease in resistant strains of S. pneumoniae has been observed in Iceland after the
introduction of pneumococcal vaccine [46]. Despite the
successful reduction in community and total antibiotic consumption in Sweden, invasive PNSP increased from 4% in 2008 to 10% in 2015, but then decreased to 5% during 2018. The fall in rate between 2015 and 2018 may also have been the effect of pneumococcal vaccin-ation, since the fall in invasive PNSP rate was not seen
in nasopharynx samples which remained at 10% [5].
Hospital consumption probably had only a minor or no effect on the PNSP rate since this is a community-acquired infection, and it is outside the hospital that antibiotic use has the greatest impact on PNSP. All
countries recommended narrow-spectrum benzylpenicil-lin for community-acquired pneumonia with no
suspi-cion of atypical pneumonia. This results in less
concomitant disruption of the bowel flora compared to broad-spectrum antibiotics [47].
The rate of MRSA was very low (0–2%) compared to
the population-weighted European mean of 17% [25],
and consequently, no Nordic country included MRSA
treatment in their guidelines for sepsis of
unknown origin.
The strengths of this study are the completeness of consumption data, large sample sizes because of the high frequencies of the pathogens chosen, and the long observation time.
Comparisons of total antibiotic use and antibiotic treatment guidelines in this survey were limited by the fact that total aggregated consumption was compared to empirical treatment guidelines for only three major indications. Another limitation regarding sepsis guide-lines is that Norwegian and Finnish guideguide-lines use SIRS-criteria [23] or modified SIRS-criteria for sepsis, severe sepsis, and septic shock while Danish, Icelandic and
Swedish use the SOFA score [24], thus limiting the
com-parison of treatment guidelines for sepsis. Furthermore, PGs in this study was structured in several different ways and varied greatly in comprehensiveness such as
recommendations for ESBL-coverage and frequency
of updates.
A Dutch study on adaptation of national to local guidelines showed that implementing national PGs at the local level by providing an online infrastructure increased compliance and comprehensiveness, as well as
the frequency of updates [48]. Our data show similarly
low levels of antibiotic resistance throughout the Nordic countries, supporting the use of Nordic guidelines. Practice guidelines for pneumonia not requiring inten-sive care are already similar in the Nordic countries and could be extended to include other indications such as pyelonephritis and sepsis. However, before implementa-tion, guidelines should be adapted to those at regional and local levels. Nordic guidelines could regularly be up-dated based on changes in levels of resistance, new breakpoints, new evidence of the most optimal dosing strategy, length of treatment, new drugs, etc. In add-ition, Nordic guidelines could include practice guidelines for special patient groups with identified risk factors or resistance problems needing broader empirical treat-ment, but also de-escalation policy and recommenda-tions for directed treatment based on aetiology and resistance patterns. Common Nordic guidelines might
also outweigh the international guidelines that are usu-ally based on other settings with higher rates of anti-biotic resistance.
This is the first Nordic study comparing ABR, anti-biotic use, and practice guidelines in Nordic countries. It shows that guidelines differ widely in Nordic countries even though levels of ABR among E. coli and K. pneumo-niae were similar. Future collaboration and research should be directed at determining which treatments of pyelonephritis and gram-negative sepsis provide the best clinical outcomes with the least unintended conse-quences including the emergence of ABR.
We believe that the data provided by this study will be helpful in designing antibiotic stewardship interven-tions aiming to preserve the low level of antibiotic resistance in hospitals in Nordic countries.
Acknowledgements
The authors are grateful for the assistance provided by the ECDC staff regarding data searches and validation.
Disclosure statement
Asko J€arvinen reports lecture honoraria from Astellas, OrionPharma, Pfizer, MSD, Sanofi and Unimedic Pharma and con-sultation fee from CSL Behring outside the submitted manuscript. Magnus Gottfredsson reports honoraria from Gilead.
Other authors declare that they have no conflict of interest.
Funding
This work has been made possible by funding from Region €Osterg€otland and VINNOVA Sweden’s innovation agency.
ORCID
Åse €Ostholm-Balkhed http://orcid.org/0000-0002-8250-8785 Magnus Gottfredsson http://orcid.org/0000-0003-2465-0422 Martin Holmbom http://orcid.org/0000-0002-3706-2294 Asko J€arvinen http://orcid.org/0000-0002-1906-7665 Mar Kristjansson http://orcid.org/0000-0002-3976-4767 Hans Joern Kolmos http://orcid.org/0000-0002-5640-953X Håkan Hanberger http://orcid.org/0000-0002-4199-0229
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